Loss of complex I due to mitochondrial DNA mutations in renal oncocytoma
Loss of complex I due to mitochondrial DNA mutations in renal oncocytoma
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DOI：
10.1158/1078-0432.ccr-07-4131
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发表时间：
2008-04-15
影响因子：
11.5
通讯作者：
Kofler, Barbara
中科院分区：
文献类型：
--
作者：
Mayr, Johannes A.;Meierhofer, David;Kofler, Barbara
目的：许多实体瘤表现出异常的有氧代谢，其特征是糖酵解能力增加和细胞呼吸减少。最近，核编码线粒体酶富马酸水合酶和琥珀酸脱氢酶的突变已在某些肿瘤类型中被发现，从而证明线粒体能量代谢与肿瘤发生之间存在直接联系。虽然线粒体基因组（线粒体DNA， mtDNA）的突变也可以影响有氧代谢，并且mtDNA的改变在肿瘤细胞中经常被观察到，但特异性肿瘤类型的呼吸链缺陷与特异性mtDNA突变之间的证据一直缺乏。实验设计：为了确定癌细胞瘤中线粒体的改变，我们研究了呼吸链酶的活性，并对15个肾癌细胞瘤组织的mtDNA进行了测序。结果：本研究表明，呼吸链复合体I （NADH/泛醌氧化还原酶）的丧失与肾嗜瘤细胞瘤有关。复合体I的酶活性在肿瘤样品中检测不到或大大降低（n = 15）。多亚基酶复合物的Blue Native凝胶电泳显示缺乏组装的复合物I。mtDNA突变分析显示在15个肿瘤中的9个肿瘤中复合物I的ND1、ND4或ND5亚基的基因发生了框移突变。结论：我们的数据表明，分离的复合物I缺失是肾嗜瘤细胞瘤的一个特殊特征，这种缺失通常是由体细胞mtDNA突变引起的。
Purpose: Many solid tumors exhibit abnormal aerobic metabolism characterized by increased glycolytic capacity and decreased cellular respiration. Recently, mutations in the nuclear encoded mitochondrial enzymes fumarate hydratase and succinate dehydrogenase have been identified in certain tumor types, thus demonstrating a direct link between mitochondrial energy metabolism and tumorigenesis. Although mutations in the mitochondrial genome (mitochondrial DNA, mtDNA) also can affect aerobic metabolism and mtDNA alterations are frequently observed in tumor cells, evidence linking respiratory chain deficiency in a specific tumor type to a specific mtDNA mutation has been lacking.Experimental Design: To identify mitochondrial alterations in oncocytomas, we investigated the activities of respiratory chain enzymes and sequenced mtDNA in 15 renal oncocytoma tissues.Results: Here, we show that loss of respiratory chain complex I (NADH/ubiquinone oxidoreductase) is associated with renal oncocytoma. Enzymatic activity of complex I was undetectable or greatly reduced in the tumor samples (n = 15). Blue Native gel electrophoresis of the multisubunit enzyme complex revealed a lack of assembled complex I. Mutation analysis of the mtDNA showed frame-shift mutations in the genes of either subunit ND1, ND4, or ND5 of complex I in 9 of the 15 tumors.Conclusion: Our data indicate that isolated loss of complex I is a specific feature of renal oncocytoma and that this deficiency is frequently caused by somatic mtDNA mutations.